Dopamine is a neurotransmitter that is found in the brains of animals, including humans, and is essential for proper nerve signal transmission. It is well-known that certain compounds block or inhibit the binding of dopamine to dopamine receptors. Such compounds are called dopamine receptor antagonists. It is also well-known that dopamine receptor antagonists are useful in the treatment of schizophrenia and psychosis.
Recently, it has been discovered that more than one type of dopamine receptor exists, and that dopamine receptor antagonists can preferentially inhibit one type of dopamine receptor over another. Two major families of dopamine receptors have been identified and named the D1 and D2 families. In the D2 family, three distinct receptor subtypes have been identified as D2, D3, and D4.
The distribution and concentration of the subtypes of receptors varies in different regions of the brain. For example, D2 receptors are found in high concentrations in the frontal cortex and limbic region, which are associated with cognitive and emotional function and also in striatal regions which are associated with motor activity.
D2 subtype receptor antagonists have been used to treat psychosis and schizophrenia, but have undesirable extrapyramidal side effects and produce tardive dyskinesia which is thought to be due to their striatal effects. In contrast, D4 receptors are found in highest concentrations in the frontal cortex and limbic regions. Therefore, D4 receptor antagonists can produce antipsychotic efficacy and lack the extra pyromidal side effects and tardive dyskinesias. Moreover, it has been observed that the levels of dopamine D4 receptors are elevated in schizophrenics.
Thus, it would be useful to have compounds that are selective D4 antagonists for the treatment of psychosis and schizophrenia.
U.S. Pat. No. 4,010,280, issued to Sumitomo Chemical Company, discloses phenoxyalkylamine derivatives. However, the compounds exemplified in that patent all have substituents at the ortho position of one of the phenyl rings.